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McElroy WT, Tan Z, Ho G, et al. Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. ACS Med Chem Lett. 2015;6(6):677-82doi: 10.1021/acsmedchemlett.5b00106.
McElroy, W. T., Tan, Z., Ho, G., Paliwal, S., Li, G., Seganish, W. M., Tulshian, D., Tata, J., Fischmann, T. O., Sondey, C., Bian, H., Bober, L., Jackson, J., Garlisi, C. G., Devito, K., Fossetta, J., Lundell, D., & Niu, X. (2015). Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. ACS medicinal chemistry letters, 6(6), 677-82. https://doi.org/10.1021/acsmedchemlett.5b00106
McElroy, William T, et al. "Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation." ACS medicinal chemistry letters vol. 6,6 (2015): 677-82. doi: https://doi.org/10.1021/acsmedchemlett.5b00106
McElroy WT, Tan Z, Ho G, Paliwal S, Li G, Seganish WM, Tulshian D, Tata J, Fischmann TO, Sondey C, Bian H, Bober L, Jackson J, Garlisi CG, Devito K, Fossetta J, Lundell D, Niu X. Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. ACS Med Chem Lett. 2015 May 12;6(6):677-82. doi: 10.1021/acsmedchemlett.5b00106. eCollection 2015 Jun 11. PMID: 26101573; PMCID: PMC4468401.
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ACS Med Chem Lett. 2015 May 12;6(6):677-82. doi: 10.1021/acsmedchemlett.5b00106. eCollection 2015 Jun 11.

Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation.

ACS medicinal chemistry letters

William T McElroy, Zheng Tan, Ginny Ho, Sunil Paliwal, Guoqing Li, W Michael Seganish, Deen Tulshian, James Tata, Thierry O Fischmann, Christopher Sondey, Hong Bian, Loretta Bober, James Jackson, Charles G Garlisi, Kristine Devito, James Fossetta, Daniel Lundell, Xiaoda Niu

Affiliations

  1. Discovery Chemistry, Structural Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

PMID: 26101573 PMCID: PMC4468401 DOI: 10.1021/acsmedchemlett.5b00106

Abstract

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.

Keywords: Interleukin-1 receptor-associated kinase 4; SAR; drug discovery; inflammation; structure-based drug design

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